Thioctic acid (alpha-lipoic acid, 6,8-dithioctic acid) has the function of a coenzyme in pyruvate-dehydrogenase complexes, alpha-ketoglutarate-dehydrogenase complexes and amino acid hydrogenase complexes, which is used as an antioxidant and a medicament for preventing or treating diabetic polyneuropathy. Thioctic acid represented by the following formula (II) has pharmacological functions which scavenge free radicals and inhibit lipid peroxidation to reduce oxidative stress, reduce protein glycosylation caused by hyperglycemia, improve glucose disposal rates to normalize neuronal ATP energy production and improve the electrical conductivity of neurons.

Thioctic acid is known as an antioxidant which inhibits oxidative stress or oxidative damage to be effective in diabetic polyneuropathy, liver disease, dementia, Alzheimer's disease, rheumatoid arthritis, increase of lipids in blood vessel, etc., and it is also reported to be effective in treating obesity or obesity-related disorders and migraine (see U.S. Pat. No. 6,251,935).
Thioctic acid, however, shows poor thermal stability and low water-solubility, thereby being difficult to provide pharmaceutical formulations. Thioctic acid has a melting point ranging from 58 to 61° C. in its racemic form and a lower melting point ranging from 47 to 49° C. in its isomer forms. The racemic and isomer forms of thioctic acid are rapidly polymerized to be inactive when they are melted. Also, thioctic acid has a problem of stimulating the esophagus of patients when it is prepared as a liquid formulation to be orally administered. Accordingly, there has been a need to develop a novel crystalline form or base addition salt of thioctic acid which has better stability and higher bioavailability.
As base addition salts of thioctic acid, U.S. Pat. No. 5,990,152 discloses metal salts, and U.S. Pat. Nos. 5,990,152, 3,562,273 and 3,718,664 teach tromethamine salt.
However, the base addition salts of thioctic acid are difficult to be prepared in solid form due to high fat-solubility of thioctic acid. Therefore, the known base addition salts of thioctic acid are mostly amorphous forms, which have low stability against heat and moisture. Among the known base addition salts, only tromethamine thioctate has a crystalline form to have an improved stability against heat and moisture, thereby being clinically used, but it requires a careful clinical use due to enzyme-inhibiting function of tromethamine (see Structure 2002, 10: 1063-1072 and Protein Peptide Lett. 2008, 15: 212-214). Also, tromethamine thioctate has a problem of significant molecular weight increase due to relatively high molecular weight of tromethamine (121.14 g/mol). Since thioctic acid is used in high dosage ranging from 100 to 600 mg depending on indication, the dosage increases by base addition amounting to 58.7% makes tromethamine thioctate difficult to be developed as a pharmaceutical formulation.
An active ingredient generally should have solubility of 3 mg/ml or higher at pH ranging from 1 to 7 in order to show optimum effect in a pharmaceutical composition considering disintegration rate during in vivo uptake. However, the known tromethamine thioctate is inferior to said solubility at pH 1.2 (stomach condition) and pH 5.2 (intestine condition), thereby showing low bioavailability on oral administration to be difficult to give sufficient effect according to the content of the active ingredient.
Therefore, there has been a need to develop a novel base addition salt having good thermal and moisture stability and high water-solubility, as well as slightly increasing dosage by the addition of a base and employing a pharmaceutically safe organic base. Particularly, in case of a drug for long-term oral administration such as thioctic acid, its stability against heat and moisture is very important since it can be stored and distributed for a long period of time before being taken.